A loss of salt and body fluid stimulates kidney regeneration in mice, a new study found. This innate regenerative ability relies on a small but potent population of kidney cells in a region known as the macula densa (MD). This region, which also plays a role in hormone secretion and filtration, may be the key to kidney regeneration.

Healing kidneys by first understanding how they got here

Chronic kidney disease (CKD) is a global health crisis. According to some estimates, it affects over 10% of the world’s population, which translates to over 800 million people; according to other estimates, it’s even worse.

“Our personal and professional mission is to find a cure for kidney disease, a growing global epidemic affecting one 1 of 7 adults, which translates to 850 million people worldwide or about 2 million in the Los Angeles area,” said Peti-Peterdi, a professor of physiology, neuroscience and medicine at the Keck School of Medicine of USC.

Traditional therapies are tailored to slow progression but there is no real cure.

“Currently, there is no cure for this silent disease. By the time kidney disease is diagnosed, the kidneys are irreversibly damaged and ultimately need replacement therapies, such as dialysis or transplantation.”

The problem is that kidneys, despite being remarkably adaptable, have a limited ability to regenerate. Instead of looking directly at how to get kidneys to regenerate, Peti-Peterdi and colleagues took a different approach: they looked at how kidneys evolved in the first place. They concluded that salt must play a key role in this process.

“From an evolutionary biology perspective, the primitive kidney structure of the fish turned into more complicated and more efficiently working kidneys to absorb more salt and water,” said Peti-Peterdi, who also directs the Multi-Photon Microscopy Core at the Zilkha Neurogenetic Institute (ZNI).

“This was necessary for adaptation to the dry land environment when the animal species moved from the salt-rich seawater. And that’s why birds and mammals have developed MD cells and this beautiful, bigger, and more efficient kidney structure to maintain themselves and functionally adapt to survive. These are the mechanisms that we are targeting and trying to mimic in our research approach.”

Salt, kidneys, and evolution

The study builds on the idea that physiological signals, such as loss of body fluid and salt, may trigger regenerative responses in the kidney. It also focuses on the macula densa (MD) cells, located at the vascular pole of each nephron. Nephrons are the structural units of the kidney. Evolution has fine-tuned these cells to sense changes in the environment and respond accordingly.

MD cells, through their unique ability to sense salt concentration, help maintain kidney function. The researchers hypothesized that these cells might also play a role in tissue regeneration by recruiting and activating progenitor cells necessary for repair.

Using advanced techniques like multiphoton microscopy and genetic cell fate tracking, the researchers observed the behavior of MD cells in living mice. They discovered that activating MD cells with low-salt diets or certain medications could recruit precursor cells — stem cells that have developed to the stage where they are committed to forming a particular kind of cell. These precursor cells are crucial for tissue repair and regeneration.

The team also found that specific proteins, which act as signals for specific genes, could be enhanced by a low-salt diet to regenerate kidney structure and function.

Researchers treated mice with focal segmental glomerulosclerosis (FSGS), a severe type of chronic kidney disease (CKD), with one of these proteins called CCN1. Additionally, they used a special medium containing substances secreted by MD cells that had been grown under low-salt conditions. This treatment led to significant improvements in kidney function, reduced the leakage of protein into the urine (albuminuria), and decreased kidney scarring (glomerulosclerosis and tubulointerstitial fibrosis).

The implications of these findings are profound. The study demonstrates that MD cells can be targeted for regenerative therapies. Granted, this was only proven in mice. However, the researchers are confident the approach could be useful for humans as well.

“We feel very strongly about the importance of this new way of thinking about kidney repair and regeneration,” said Peti-Peterdi. “And we are fully convinced that this will hopefully end up soon in a very powerful and new therapeutic approach.”

Journal Reference: Georgina Gyarmati et al, Neuronally differentiated macula densa cells regulate tissue remodeling and regeneration in the kidney, Journal of Clinical Investigation (2024). DOI: 10.1172/JCI174558